JPH11512399A - Pyrimidinecarboxamides and related compounds and methods for treating inflammatory conditions - Google Patents

Abstract

(57) SUMMARY Disclosed are compounds that generally have utility as anti-inflammatory agents, more particularly for the prevention and / or treatment of immuno-inflammatory and autoimmune diseases. The compound is a pyrimidine or pyrazine containing compound and, in one embodiment, its carboxamide. A method for preventing and / or treating an inflammatory condition by administering an effective amount of a compound of the present invention, preferably in the form of a pharmaceutical composition, to an animal in need of the prevention and / or treatment of the inflammatory condition is also provided. Disclosed.

Description

DETAILED DESCRIPTION OF THE INVENTION                 Pyrimidinecarboxamide and related compounds                   And methods for treating inflammatory conditionsTechnical field   The present invention generally blocks intracellular signaling and activation of transcription factors. Compounds and methods for preventing or treating immune inflammatory and autoimmune diseases About the law.Background of the Invention   Cell proliferation, differentiation, response to bioregulatory molecules, infectious agents and physiological stress The signals required for transcription are involved in altering the rate of gene expression. Such a signa Ability to respond appropriately to mitotic events challenges the survival of cells and ultimately organisms . Perturbations in the normal regulation of these specific gene responses are associated with acute and chronic diseases. It can cause a pathogenic event leading to the disease.   Continuous activation of T cells in certain autoimmune diseases or chronic inflammatory conditions Is ultimately the self-perpetuating destruction of normal tissues or organs. on). It is responsible for adhesion molecules, leukocyte chemotaxis, leukocyte activation and inflammation. Produced by induction of production of the medium. All these events involve cytokines It is regulated at the level of transcription for the production of new proteins. Cytokine In addition, the production of many other cellular regulators is a protein known as the transcription factor (TF). It is controlled by a family of proteins. When these transcription factors are activated, Binds to specific regions on DNA, and acts as a molecular switch or messenger Act to induce or upregulate gene expression. Activities of these TFs Sexualization is caused by various external factors, including physiological stress, infectious agents, and other bioregulatory molecules. Caused by a signal. Once the plasma membrane receptor is activated, the protein A cascade of kinases and second messengers is induced, followed by RNA Transcripts are produced. The end result is translation and RNA transcript processing. Via Is the production of proinflammatory proteins.   This activation system is sometimes very crude. For example, for an external signal A particular set is a simple set for inducing many proteins that can respond to a given disease. It can give rise to one transcription factor. Therefore, by destroying the product of activated TF Regulating this process reduces the production of related pathological proteins. , Thereby stopping or reversing the course of the disease.   Two transcription factors, NFκB and AP-1, are many pro-inflammatory cytokines and immune It has been shown to regulate the production of related proteins that are elevated in inflammatory diseases . These TFs are used in various cell types for interleukin-1 (IL-1), 2 (IL-2), tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and Regulates Tarleukin-8 (IL-8) levels. For example, NFκB and other related complexes Is the function of the product in protection and growth, Involved in the rapid induction of genes. Similarly, AP-1 activates T cells During interleukin, regulates transcription of interleukin-2 (IL-2) and tumor necrosis factor (TNF-α) It has an important role. In addition, TNF-α and IL-1 are the promoters of these genes. , A single AP-1 binding site in the It is a potent activator of stromelysin gene expression. Therefore, NFκB And / or inhibitors of AP-1 activation modulate the activity of a series of proteinases. Consistently suppress. In addition, cell adhesion molecules are also controlled by these TFs. This All of these proteins are osteoarthritis, transplant rejection, ischemia, reperfusion injury, Trauma, certain cancer and viral diseases, and rheumatoid arthritis, multiple Self like keratosis, psoriasis, inflammatory bowel disease, glomerulonephritis, lupus and juvenile diabetes It has been shown to play a role in diseases, including immune diseases. In summary, these The role of TF is to act as a transducer for certain stimuli , Which leads to an immune, inflammatory, and acute phase response.   Many diseases are caused by inappropriate production of proteins, and Therapeutic approaches involve inhibiting the function or activity of individual effector proteins. And was focused on. These measures have not been proven to be effective. And sometimes associated with many unwanted side effects. Therefore, immune inflammatory diseases and Need for new therapies for the prevention and / or treatment of cancer and autoimmune diseases Exists. More specifically, preferably by inhibiting transcription at an early stage That interfere with the production of proteins associated with immunoinflammatory and autoimmune diseases There is a need for In addition, these compounds are more likely than NFκB and AP-1. Should inhibit kinases that regulate the activation of TF. The present invention Meet the requirements and provide further related benefits.Summary of the Invention Briefly, the present invention inhibits the activation of transcription factors (TF), especially NFκB and AP-1 Compounds, and these are via inhibition of a specific family of kinases It is thought to work. This can include IL-1, IL-2, IL-8 and / or TNFα ( These include rheumatoid arthritis, osteoarthritis, related autoimmune diseases and Which contribute to tissue and organ damage associated with diseases such as tissue rejection). This results in a decrease in the number of proinflammatory proteins. Thus, the compounds of the present invention include, for example, Useful in preventing organ and tissue rejection for transplantation. Further, the compounds of the present invention The product may also be used in the prevention and / or treatment of immunoinflammatory and autoimmune diseases. And has general activity like anti-inflammatory factors.   In one embodiment of the present invention, compounds having the general structure (I) Show. Where B is N, A is C-R₆And B is C-R₁, Then A is N and Then R₁, R_Two, R_Four, R_Five, And R₆Is defined by the following detailed description. You.   In another embodiment, one or more compounds of the present invention are pharmaceutically or prophylactically received. Disclosed are pharmaceutical compositions comprising a combination with an acceptable carrier or diluent.   In another embodiment, an effective amount of a compound of the present invention is administered to a warm-blooded animal in need thereof. A method for preventing and / or treating inflammatory conditions by administering Show. Such inflammatory conditions include both immuno-inflammatory conditions and autoimmune diseases . In practicing the disclosed method, the compound is warmed, preferably in the form of a pharmaceutical composition. Administered to blood animals.   These and other aspects of the invention are described with reference to the accompanying drawings and the following detailed description. And clarify.BRIEF DESCRIPTION OF THE FIGURES   FIG. 1 illustrates a reaction scheme for the synthesis of a representative pyrimidine-containing compound of the present invention. I do.   FIG. 2 illustrates a reaction scheme for the synthesis of a representative pyrazine-containing compound of the present invention. You.   FIG. 3 shows the ability of representative compounds of the present invention to inhibit NFκB and AP-1 activation. Illustrate the forces.   FIG. 4 illustrates the ability of representative compounds of the invention to inhibit IL-2 and IL-8. You.   FIG. 5 shows dose-dependent inhibition of alloantigen-induced PLN proliferation of representative compounds of the present invention. Illustrates the ability to causeDetailed description of the invention   As mentioned above, the compounds of the present invention block the activity of transcription factors (TF). And, thus, are generally useful as anti-inflammatory agents, and Prevention and prevention of various conditions, including but not limited to autoimmune diseases And / or useful in therapy. Compounds are in such an early stage Works by inhibiting the transcription of harmful proteins associated with a condition or disease it is conceivable that. It is a kinase that regulates the activation of TFs such as NFκB and AP-1 It is believed that this is achieved by inhibiting zeolites. Production of these activated TFs A series of immuno-inflammatory and pro-inflammatory cytokines, Self Synthesis of pathological proteins associated with autoimmune diseases is effective at the transcriptional level Blocked. Therefore, the compounds of the present invention are useful for treating immune inflammatory diseases (eg, rheumatoid arthritis). Osteoarthritis, osteoarthritis, and transplant rejection (tissues and organs) Active in both preventing and treating epidemics (eg, multiple sclerosis) .   The compounds of the present invention are generally represented by the following general structure (I): Where B is N, A is C-R₆And B is C-R₁, Then A is N and Then R₁, R_Two, R_Four, R_Five, And R₆Is defined below. Therefore, A is C-R₆ And when B is N, the structure (I) comprises a pyrimidine having the structure (II) A is N and B is C-R₁Where structure (I) has the structure A pyrazine-containing compound having (III):   In the above structures (I), (II) and (III), R_FiveIs the following chemical moiety (i ) To (iv). here   R₇Is hydrogen, -CH_Three, And -CH_TwoC₆H_FiveSelected from; and   R₈Is hydrogen and unsubstituted or substituted C_1-8Alkyl, C_6-12Aryl, C_{7- 12} Aralkyl, C_3-12Heterocycle, and C_4-16Selected from heterocyclic alkyls.   The compounds of the present invention are pharmaceutically and prophylactically acceptable salts of compounds of structure (I) Further included. Compounds of structure (I) include proton donating groups (eg, carboxylic acid groups) and And / or proton accepting groups (e.g., having a free lone pair of electrons such as an amino group). And a salt of the compound of structure (I) It can be formed and used in practice. Therefore, the compound of the present invention is prepared by adding a base. In the form of a salt (ie, a salt of a proton donating group) or an acid addition salt (ie, a proton acceptor In their free acid or free base form. Can get.   The acid addition salt of the free base amino compound of the present invention can be prepared by a method well known in the art. It can be prepared and formed from organic or inorganic acids. Suitable organic acids are acetic acid, Scorbic acid, benzenesulfonic acid, benzoic acid, fumaric acid, maleic acid, methane Sulfonic acid, and succinic acid. Suitable inorganic acids are hydrochloric acid, hydrobromic acid , Sulfuric acid, phosphoric acid, and nitric acid. Of the free acid carboxylic acid compound of the present invention Base addition salts may also be prepared by methods well known in the art and include organic or inorganic salts. It can be formed from a base. Thus, the compounds of the present invention may also include inorganic bases (eg, Thorium, potassium, lithium, ammonium, calcium, magnesium, iron , Hydroxides or other salts such as zinc, copper, manganese, and aluminum), And salts derived from organic bases such as substituted ammonium salts.   As used herein, the above terms have the following meanings:   "C_1-8"Alkyl" means a straight or branched, cyclic or cyclic containing 1 to 8 carbon atoms. Is an acyclic, saturated or unsaturated carbon chain. In one embodiment, C_1-8A Alkyl is methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. Fully saturated straight-chain alkyl selected from In other embodiments, C_{1 -8} Alkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Methylenecyclopropyl, and methylenecyclohexyl ( (But not limited to) fully saturated cyclic alkyl. Another embodiment In C_1-8Alkyl is isopropyl, sec-butyl, isobutyl, tert- Selected from, but not limited to, butyl, isopentyl, and isohexyl. (Unspecified) is a fully saturated branched alkyl. In still another embodiment, , C_1-8Alkyl is ethylenyl, propylenyl, 1-butenyl, 1-pentenyl, and And 1-hexenyl, but is not limited to, It is Luquil.   "C_6-12"Aryl" is an aromatic moiety having 6 to 12 carbon atoms. One In embodiments of C_6-12Aryl is phenyl, tetralinyl, and naph Selected from, but not limited to, thallenyl. In a preferred embodiment Then C_6-12Aryl is phenyl.   "C_7-12"Aralkyl" has 7-12 carbon atoms, aliphatic units and aromatic units An arene having both family units. In one embodiment, C_7-12Aral Kills include benzyl, ethylbenzyl, propylbenzyl, and isobutyl Selected from (but not limited to) Jill.   "C_3-12“Heterocycle” has a ring made of one or more atoms and has 3 to 12 carbon atoms. It is a compound having an atom. In one embodiment, C_3-12Heterocycle, pylori , Furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl , Pyrrolidinyl, pyridinyl, pyrimidinyl, and purinyl (But not limited to). In other embodiments, C_3-12The heterocycle is Structure Having:   "C_4-16`` Heterocyclic alkyl '' is C_1-8C attached to alkyl_3-12Containing heterocycle It is a compound. In one embodiment, C_4-16Heterocyclic alkyl has the following structure Is methylenefuran:   "Replace" C_1-8Alkyl, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle Or C_4-16Heterocyclic alkyl includes halogen (including -F, -Cl, -Br, and -I), -OH , -R, -OR, -COOH, -COOR, -COR, -CONH_Two, -NH_Two, -NHR, -NRR, -SH, -SR, -SOOR , -SO_ThreeHaving at least one hydrogen replaced with a substituent selected from R and -SOR C_1-8Alkyl, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle, or C_4-16 A heterocyclic alkyl wherein each occurrence of R is unsubstituted or substituted as defined above. Exchange C_1-8Alkyl, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle, or C_4-16 Independently selected from heterocyclealkyl. In one embodiment, the substituted C_1-8A Lucil is -CF_ThreeAnd -C_TwoF_FiveC including (but not limited to)_1-8Haloalk It is.   In the above structure (II), R_2aIs halogen, unsubstituted or substituted C_1-8Al Kill, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle or C_4-16Heterocycle R, selected from alkyl, -CN, -OR, -NHR, -NRR, and -NRNCOR. Is unsubstituted or substituted C as defined above_1-8Alkyl, C_6-12Aryl, C_7-12A Ralkir, C_{3- 12} Heterocycle, or C_4-16Independently selected from heterocyclealkyl. One embodiment In R_2aIs -Cl, -F, -CN, and -CF_ThreeIs selected from   In the above structure (III), R_2bIs a halogen such as -Cl or -F.   In the above structure (II), R_4aIs hydrogen, halogen, unsubstituted or substituted C_1-8 Alkyl, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle or C_4-16Complex Selected from ring alkyl, -CN, -OR, -NHR, -NRR, and -NRNCOR, appearing here R is unsubstituted or substituted C as defined above._1-8Alkyl, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle or C_4-16Independently selected from heterocyclic alkyl Selected. In one embodiment, R_4aIs hydrogen, -CH_Three, -CF_Three, -C_TwoF_Five, -C_TwoH_Five , -C₆H_Five, And -CH_TwoC₆H_FiveIs selected from   In the above structure (III), R_4bIs hydrogen, halogen, -CN, and unsubstituted Or substitution C_1-8Alkyl, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle, if C_4-16Selected from heterocyclic alkyls.   In the above structures (I) and (II), R₆Is hydrogen, halogen, and none Exchange or substitution C_1-8Alkyl (this is C_1-8Haloalkyl (-CF_ThreeAnd -C_TwoF_FiveNo Una) (including, but not limited to). One embodiment In R₆Is hydrogen, -Cl, -F, -CH_Three, And -CF_ThreeIs selected from   In the above structures (I) and (III), R₁Is hydrogen, -CH_Three, -CF_ThreeAnd -C_TwoH_Five Is selected from   In one embodiment, the compounds of the present invention have the above structure (II), wherein R₁Is the chemical moiety (i). In this embodiment, disclosed herein. The compound has the following structure (IV): Where R_2a, R_4a, R₆, R₇, And R₈Is as defined above. Favorable fruit In embodiments, representative compounds of structure (IV) are represented by R 1 shown in Table 1 below._2a, R_4a, R₆, R₇, And R₈Including parts. Where X, Y and Z are the same or different and are hydrogen, -OH, -R, -OR , -COOH, -COOR, -COR, -CONH_Two, -NH_Two, -NHR, -NRR, -SH, -SR, -SOOR, -SO_ThreeR, You And -SOR are independently selected, wherein each R that appears is unsubstituted or substituted C_1-8A Lucil, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle, or C_4-16Heterocycle Selected independently from the Luquil.   In a preferred embodiment of the compounds disclosed in Table 1 above, X, Y and Z are , Identical or different, and -H, -Cl, -F, -CF_Three, -OH, -CH_Three, And -O CH_ThreeIndependently selected from In a further preferred embodiment, R₈Is a 3,5-bi (Trifluoromethyl) phenyl moiety or 3-trifluoromethyl-5-halo-fe Nyl moiety.   As mentioned above, in one embodiment of the present invention, the compound has the structure (II) Having. In one aspect of this embodiment, R_4aIs -CF_ThreeAnd R_2aIs -Cl is there. Such compounds include (but are not limited to): : 2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-bistrifluoromethylphenyi L) pyrimidinecarboxamide; 2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-di (Chlorophenyl) pyrimidinecarboxamide; 2-chloro-4-trifluoromethyl-5 -N- (4'-trifluoromethylphenyl) pyrimidinecarboxamide; 2-chloro-4- Trifluoromethyl-5-N- (phenyl) pyrimidinecarboxamide; 2-chloro-4-to Trifluoromethyl-5-N- (cyclohexyl) pyrimidinecarboxamide; 2-chloro- 4-trifluoromethyl-5-N- (3 ', 4', 5'-trichlorophenyl) pyrimidinecarbox Samide; 2-chloro-4-trifluoromethyl-5-N- (benzyl) pyrimidinecarboxa Mido; 2-chloro-4-trifluoromethyl-5-N- (4 '-(2', 1 ', 3'-benzothiadiazo L) pyrimidinecarboxamide; 2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-di (Chloro-6'-hydroxyphenyl) pyrimidinecarboxamide; 2-chloro-4-trif Fluoromethyl-5-N- (5 ′-(3′-methylisoxazole) pyrimidinecarboxamide; 2-chloro-4-trifluoromethyl-5-N- (3'-N-acyl-4'-fluoroaniline) pyri Midinecarboxamide; 2-chloro-4-trifluoromethyl-5-N- (3-trifluoro Methyl-5'-ethoxycarbonylphenyl) pyrimidinecarboxamide; 2-chloro- 4-trifluoromethyl-5-N- (3'-trifluoromethyl-5- (carboxamide) phenyl L) pyrimidinecarboxamide; 2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-di Chlorophenyl) -N- (methyl) pyrimidinecarboxamide; and 2-chloro-4-to Trifluoromethyl-5-N- (3 ', 5'-dichlorophenyl) -N- (benzyl) pyrimidinecar Boxamide.   In another aspect of this embodiment, R_4aIs -CF_ThreeAnd R_2aIs the part other than -Cl ( moiety). Such compounds include (but are not limited to) Not): 2-fluoro-4-trifluoromethyl-5-N- (3 ', 5'-bistrifluoro Methyl) pyrimidinecarboxamide; 5- (3 ', 5'-bis (trifluoromethyl) phena Sil) -2-methoxy-4-trifluoromethylpyrimidine; 4-trifluoromethyl-5- N- (3 ', 5'-dichlorophenyl) pyrimidinecarboxamide; 2-dimethylamino-4- Trifluoromethyl-5-N- (3 ', 5'-dichlorophenyl) pyrimidinecarboxamide ; 2-triethylammonium chloride-4-trifluoromethyl-5-N- (3 ', 5'-di (Chlorophenyl) pyrimidinecarboxamide; 2-cyano-4-trifluoromethyl-5 -N- [3 ', 5'-(bistrifluoromethyl) phenyl] pyrimidinecarboxamide; 2- Hydrazino-4-trifluoromethyl-5- [N- (3 ', 5'-dichlorophenyl) pyrimidine- 5-carboxamide; 2- [N- (1-aminocitraconamide)]-4-trifluoromethyl- 5- [N- (3 ', 5'-dichlorophenyl) pyrimidine-5-carboxamide; and 2-amino Phenyl-4-trifluoromethyl-N- (3 ', 5'-dichlorophenyl) pyrimidine-5-ca Luboxamide.   In another aspect of this embodiment, R_2aIs -Cl and R_4aIs -CF_ThreeOther than Part. Such compounds include (but are not limited to) Not): 5-N- (3 ', 5'-bis (trifluoromethyl) phenyl) -2,4-dichloro-6-meth Tylpyrimidinecarboxamide; 2-chloro-4-methyl-5-N- (3 ', 5'-bistrifur (Oromethyl) phenyl) pyrimidinecarboxamide; 2,4-dichloro-5-N- (3 ′, 5′-bi 2- (trifluoromethyl) benzyl) pyrimidine-5-carboxamide; B-4-phenyl-5-N- (3 ', 5'-bistrifluoromethyl) phenyl) pyrimidinecar Boxamide.   In another embodiment, the compounds of the invention have the above structure (III). this In one aspect of the embodiment, R₁Is hydrogen, -CH_Three, And -CF_ThreeSelected from . Such compounds are pyramid corresponding to the pyrimidine-containing compounds disclosed above. Including, but not limited to, gin-containing compounds. One of structure (III) Real In embodiments, R_2bIs -Cl and R_4bIs -CF_ThreeAnd R_FiveIs the above structure This is the part (i).   A small number of compounds within the above structure (I) have been previously disclosed, and And / or commercially available. However, such compounds are useful for the present invention. Is not relevant or has no usefulness. Therefore, the conversion within the range of the structure (I) Compounds which have been found to be useful are particularly excluded from the novel compounds of structure (I). Removed. However, such compounds have been disclosed for their utility. To the extent they do not, they are included in the various methods of the present invention.   For this purpose, the novel compounds according to the invention are represented by the structure (IV) Not including compounds that are:₇And R₈Are both hydrogen; and R_2aIs not replaced With a linear or branched, acyclic saturated C_1-3Alkyl (ie -CH_Three, -CH_TwoCH_Three,-(C H_Two)_TwoCH_Three, And -CH (CH_Three)_Two), -N (CH_Three)_Two, -N (CH_TwoCH_Three)_Two, And -OR here And R is as defined above). Similarly, a new structure (IV) The compound requires the following conditions: (a) R_2aIs -Cl, and R₆Where is -H If R_4aIs -CF_Three, -Cl, -CH_Three, Or -C (CH_Three)_ThreeNot (b) R_2aBut -Cl And R_4aAnd R₆Are both -H, then R₈Is -CH (CN) C₆H_FiveBut-(CH_Two)_FiveCH_Three Not even; and (c) R_2aIs -Cl, and R_4aR is -Cl₆Is -Cl Also -CH_TwoNot Cl.   The novel compounds of the present invention also include R_FiveIs part (iii) and (a) R_2aBut -CH_Three, -OCH_Three, Or -N (CH_Three)_TwoOr (b) R₈Is -H, or -CH_Threeso Excludes compounds of structure (II) in some cases.   Furthermore, R_FiveWhen is a component (i), the novel compounds of structure (III) Requires: R_2bR is -Cl_4aAnd R₁Are both hydrogen No.   The compounds of the present invention may be prepared using techniques known to those skilled in the art of organic synthesis as well as Can be made by the following synthetic route. Compound contains pyrimidine for convenience The (structure (II)) compound and the pyrazine-containing (structure (III)) compound are shown below. Separated. The pyrimidine-containing compound of the present invention is prepared by the reaction scheme shown in FIG. Can be prepared as illustrated. Generally, commercially available β-ketoester 1 is A with triethyl orthoformate (or substituted orthoformate) Both are heated to a high temperature (75-110 ° C.) to give ureide derivative 2. This intermediate is Sodium alkoxide such as thorium ethoxide in alcoholic solvent Treatment at 0 ° C. gives 2-hydroxypyrimidine ester 3, which is Treat with a chlorinating reagent such as xycyclosilide at high temperature (75-120 ° C) to give 2-chloro This gives the pyrimidine ester 4. 2-hydroxypyrimidine ester 3 also contains water With a mild base such as lithium oxide, sodium hydroxide, or potassium carbonate Work-up gives the corresponding acid 3A, which is then converted to a phosphorous oxyclosilide or Is a chlorinating reagent such as thionyl chloride in an inert solvent or neat at 25-75 ° C. Convert to acid chloride 5. Compounds of structure 6 use standard conditions known in the art In the presence of a base such as potassium carbonate or dimethylaminopyridine (DMAP) At 25-40 ° C. in an aprotic solvent such as methylene chloride or EtOAc. Can be prepared by reacting the acid chloride 5 with an amine followed by standard work-up .   Alternatively, the pyrimidine-containing compounds of the present invention can also be prepared by the following combination procedure. Can be made. Commercially available and / or easily synthesized amines, anilines, and And related compounds were prepared by acid chloride 5 in EtOAc in the presence of basic Amberlyst 21 resin. Can be reacted with The reaction is quenched with 50 μL of water, and the final product is Obtained and concentrated. This procedure is for a 96-well (1 mL deep well) plate And the final product is isolated as a dry powder. TLC analysis for each compound Performed to show purity, and GC / MS and HPLC analysis indicate that the desired product is Synthesized (mass spectrum analysis, molecular weight) and more than 80% pure It represents that. By this method, 80 pyrimidine-containing compounds can be loaded into one 96-well It can be synthesized routinely simultaneously in the plate.   Further, compound 4 reacts with various nucleophiles at room temperature in an aprotic solvent. , Derivative 7. These compounds are hydrolyzed with a base to have structure 8. Compound. The compound of structure 8 can be converted to the acid chloride described above, and Reacting with various amines using known conditions, including the combination procedure described above, This gives a compound having structure 9. Alternatively, the compound of structure 7 is also a β-keto Stele 1 was prepared in a continuous manner in DMF with triethyl orthoformate and anhydrous vinegar. Reaction with acid or N, N-dimethylformamide dimethyl acetal gives intermediate 10 To Can be prepared. Intermediate 10 in various alcoholic solvents To give a compound of structure 7 by addition of a base.   The pyrazine-containing compound of structure (III) is as illustrated in the reaction scheme of FIG. Can be prepared. The synthesis of these compounds is a readily available pyruvate derivative You can start with 12. These compounds are used in alcoholic solvents (such as MeOH). ) In the presence of an acid (such as HCl) at room temperature (25-60 ° C) at room temperature. Condensed with diamino-2-substituted ethane 13 to provide the cyanopyrazine of structure 14. Pyrazines are then heated at high temperatures (70-110 ° C) with strong salts such as sodium hydroxide in water. Can be converted to the corresponding carboxylic acid 15 using a group, or a strong acid such as hydrochloric acid . These carboxylic acids are then converted to POCl_ThreeOr SOCL_TwoUsing a chlorinating reagent such as To the 5-chloro-2-carbonyl acid chloride derivative 16. Compound 16 at room temperature , EtOAc or CH_TwoCl_TwoWith various amines or anilines in an inert solvent such as Upon treatment, a compound of structure 17 is provided.   The carboxylic acid of structure 15 can also be_TwoAnd MeOH, It can be converted to hydroxyester 18. Compound 18 in SOCl in the presence of DMF_TwoAnd PO Cl_ThreeTreatment with a chlorinating reagent such as Compound 19 also has M In a protic solvent such as eOH, use a mild solvent such as potassium carbonate. Using a base, then oxidize at room temperature in an inert solvent such as methylene chloride. Treatment with a chlorinating reagent such as salyl chloride can be converted to acid chloride 16.   The pyrazine-containing compounds of the present invention may also be prepared by appropriate combination techniques as described. Can be synthesized. That is, commercially available and / or easily synthesized amines, Nilin and related compounds were acidified in EtOAc in the presence of basic Amberlyst 21 resin. Can react with chloride 16. The reaction is quenched with 50 μL of water and the final product Is obtained in the organic layer and concentrated. This procedure is 96 wells (1 mL deep well) It can be performed in a plate and the final product is isolated as a dry powder. TLC analysis Performed on each compound to indicate purity, and GC and HPLC analysis performed on the desired product Was synthesized (mass spectrometry, molecular weight), and It represents that. By this method, 80 pyrazine-containing compounds can be added to one 96-well It can be synthesized routinely simultaneously in the plate.   Once synthesized, the compounds of the present invention can be used to produce warm blood by various techniques known to those skilled in the art. It can be formulated for administration to an object. In one embodiment, the compound is Or in the form of a pharmaceutical composition for therapeutic use, and at least one of the invention The compound is contained in combination with a pharmaceutically acceptable carrier or diluent. this The compounds, when administered to animals, are effective in preventing or treating the condition in question. It is present in the composition in an amount. Preferably, the composition comprises a compound of the invention administered. Depending on the route of administration, amounts in the range of 0.01 to 250 mg per dose and more preferably Preferably, it is contained in an amount of 1 to 60 mg. Appropriate concentrations, dosages and methods for administration are known to those of ordinary skill in the art. Can be easily determined by   Suitable carriers or diluents are well known to those skilled in the formulation arts. liquid For compositions formulated as a solution in the body, acceptable carriers or diluents Contains saline or sterile water and optionally contains antioxidants, buffers, bacteriostats and the like. And other common additives. The composition of the present invention also comprises a compound of the present invention. In addition to diluents, dispersants and surface active agents, binders And may be formulated as pills, capsules, granules or tablets, containing a lubricant You. Those skilled in the art will further appreciate that the compounds of the present invention may be prepared by any suitable method and ngton's Pharmaceutical Sciences, edited by Gennaro, Mack Publishing Co., Easton , PA, 1990, incorporated herein by reference. And may be formulated according to practice.   In other embodiments, the invention provides methods for preventing or treating various conditions. I do. Such methods should be used in an amount sufficient to prevent or treat the condition. Administering a light compound to a warm-blooded animal in need thereof. This way Is a systemic compound of the invention, preferably in the form of a composition as disclosed above. Including administration. As used herein, systemic administration is oral and parenteral (pare). ntal). Pharmaceutical compositions suitable for oral administration include powders, granules, pills , Tablets and capsules as well as liquids, syrups, suspensions and emulsions. this These compositions also include flavors, preservatives, suspending agents, thickening and emulsifying agents, and pharmaceuticals. May include other additives that are acceptable. For parenteral administration, the compounds of the invention In addition to the compounds of the invention, buffers, antioxidants, bacteriostats and usually such solutions Use Aqueous injectable solutions can be prepared that can contain other additives used.   As mentioned above, the compounds of the present invention may have a wide variety of disorders, diseases and / or Or it can be used to prevent or treat a disease. In particular, this compound Rheumatoid arthritis, osteoarthritis, tissue and / or organ transplant rejection, Sepsis, ARDS, asthma, trauma, oxidative stress, cell death, radiation damage , Ischemia, reperfusion, cancer, viral infections, and autoimmune diseases (eg, psoriasis, inflammation Prophylaxis or treatment of sexual bowel disease, glomerulonephritis, To warm-blooded animals.   The compounds of the present invention can be used for their prophylactic use by known and accepted techniques. And / or screened for their ability to act as therapeutically active agents. Can be For example, the compound demonstrates the anti-inflammatory and immunosuppressive properties of the compound. It can be evaluated in the indicated in vitro and / or in vivo assays. For this purpose , Such compounds have the ability of the compound to prevent NFκB and AP-1 activation. Can be first evaluated in a number of cell-base assays to determine 56). Next, the cytokine levels of this compound (IL-2 and Ability to reduce (such as IL-8), which is known to be elevated in certain disease states The force can be determined (see Example 57). And this compound is irritating and And can be assessed by appropriate animal models, including rodent models of immunosuppression ( See Example 58).   For example, has utility for the treatment of immunosuppressants and rheumatoid arthritis (RA) For other drugs, a number of studies have been performed on the activity of such drugs. It should be noted that For this purpose, cyclosporin A has been available since the late 1970s. Has been used in clinical trials as a second-line drug and It is recommended that it be used only in patients with sex RA. Thus, the embodiment 58 was performed using cyclosporin A as a positive control. recent years A review of such immunosuppressants includes relevant assays for it, R. P. Carlson in Exp. Opin. Invest. Drugs 4 (9): 853-859, 1995 (Incorporated herein by reference in its entirety, including references).   The following examples are presented for purposes of illustration, but not limitation.                                  Example   Summarizing the following examples, Examples 1-54 show representative compounds of the invention and Disclose the synthesis of the intermediate product; Example 55 discloses a representative compound combination Examples 56-57 disclose synthetic compounds by chemical techniques. Discloses the ability of the products to inhibit NFκB, AP-1 and cytokines; and 58 represents a graft versus host disease and contact susceptibility model of a representative compound of the invention. The activity in both is disclosed.                                 Example 1 2-chloro-4-trifluoromethyl-5-N- [3 ', 5'-bis (trifluoro              Oromethyl) phenyl] pyrimidinecarboxamide   3,5-bistrifluoromethylaniline (0.20 g, 0.92 mmol), Amberlyst  To a mixture of A-21 ion exchange resin (0.02 g) in EtOAc (5 ml) was added 2-chloro- 4-trifluoromethylpyrimidine-5-carbonyl chloride (0.27 g, 1.13  mmol) in EtOAc (5 ml) was added. The mixture was stirred for 0.5 h, then water (20 m The reaction was stopped in l). The organic layer was separated and MgSO_FourDried over, filtered and solvent Was removed under reduced pressure. EtOH / H_TwoRecrystallized from O to give a white solid Thus, the title compound (0.21 g, yield 53%) was obtained. 162-163 ° C.                                 Example 2                 2-chloro-4-trifluoromethyl-5-     N- (4'-trifluoromethylphenyl) pyrimidinecarboxamide   4-trifluoromethyl instead of 3,5-bistrifluoromethylaniline Aniline (0.1 g, 0.41 mmol) and acid chloride (0.10 g, 0.41 mmol) Except that used, the title compound was prepared as described in Example 1 to give a yield of 24%. Was. Mp 172-173 ° C.                                 Example 3                   2-chloro-4-trifluoromethyl-               5-N- (phenyl) pyrimidinecarboxamide   Aniline (0.04 g, 0.39 mmol) and acid chloride (0.22 g, 0.90 mmol) The title compound was prepared as described in Example 1 except that Obtained. 108-181 ° C.                                 Example 4                   2-chloro-4-trifluoromethyl-            5-N- (cyclohexyl) pyrimidinecarboxamide   Cyclohexylamine (0.02 g, 0.18 mmol) and acid chloride (0.05 g,  The title compound was prepared as described in Example 1 except that 0.22 mmol) was used. , Yield 33%. 150-151 ° C.                                 Example 5                   2-chloro-4-trifluoromethyl-               5-N- (benzyl) pyrimidinecarboxamide   Benzylamine (0.09 g, 0.92 mmol) and acid chloride (0.25 g, 1.0 m The title compound was prepared as described in Example 1 except that 8% was obtained. 152-153 ° C.                                 Example 6                   2-chloro-4-trifluoromethyl-        5-N- (3 ', 4', 5'-trichlorophenyl) pyrimidinecarboxamide   3,4,5-trichloroaniline (0.15 g, 0.61 mmol) and acid chloride (0.15 g, 0.61 mmol), except that the title compound was used as described in Example 1. Was prepared and a yield of 55% was obtained. 200-201 ° C.                                 Example 7                   2-chloro-4-trifluoromethyl-     5-N- (4- (2 ', 1', 3'-benzothiadiazole)) pyrimidinecarboxamide   4-amino-2,1,3-benzothiadiazole (0.01 g, 0.07 mmol) and Except that acid chloride (0.025 g, 0.10 mmol) was used, The title compound was prepared as above to give a 60% yield. 179-180 ° C.                                 Example 8   2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-dichloro-            6'-hydroxyphenyl) pyrimidinecarboxamide   3,5-dichloro-6-hydroxyaniline (0.02 g, 0.11 mmol) and acid Chloride (0.04 g, 0.16 mmol) and chromatography (SiO_Two, 1: 1 hexane / EtOAc), except that purification was carried out as described in Example 1. The title compound was prepared to give the compound in 10% yield. Melting point 211-213 ° C.                                 Example 9                   2-chloro-4-trifluoromethyl-     5-N- [5 '-(3'-methyl-isoxazole)] pyrimidinecarboxamide   5-amino-3-methylisoxazole) (0.02 g, 0.17 mmol) and acid As described in Example 1, except that chloride (0.03 g, 0.10 mmol) was used. The title compound was prepared in a yield of 75%. 170-171 ° C.                                Example 10 2-chloro-4-trifluoromethyl-5-N- (3'-N-acyl-4'-f                Fluoro-aniline) pyrimidinecarboxamide   2-fluoro-5-nitroaniline (1.97 g, 12.60 mmol) and Ac_TwoO / Pi A solution of a 1: 1 mixture of gin (20 ml) was stirred for 18 hours. The precipitate obtained is filtered And MeOH to give N-acyl-2-fluoro-5-nitroaniline.   N-acyl-2-fluoro-5-nitroaniline (0.99 g, 5.00 mmol) was added to EtO H (25 ml) and 10% Pd / C (0.12 g) was added and the solution was_Two5 o'clock below While stirring. The suspension was filtered through celite and the filtrate was evaporated to dryness . The resulting oil is chromatographed (SiO_Two, 1: 3 hexane / EtOAc) and yellow 3-N-Acyl-4-fluoro-aniline was obtained as a color oil. Next, The niline derivative is converted to 2-chloro-4-trifluoromethylpyrimidine-5-carboni Conjugation with ruchloride as described in Example 1 afforded the title compound in 47% yield. . 126-127 ° C.                                Example 11 2-chloro-4-trifluoromethyl-5-N- (3'-trifluoromethyl-          5'-carboxamidophenyl) pyrimidinecarboxamide   3-Nitro-5-trifluoromethylbenzoic acid (1.00 g, 4.25 mmol) in CH_TwoCl_Two (50 ml) solution, oxalyl chloride (1.45 g, 13.8 mmol) was added, followed by DMF ( 3 drops) were added. The evolved gas was immediately discharged and the reaction was stirred for 18 hours. Reduce solvent The oil was removed under pressure and the resulting oil was dissolved in THF (80 ml) and cooled to 0 ° C. cold To the cooled solution was added NH in THF (15 ml)._FourOH (22 ml) was added dropwise and the mixture was left at room temperature for 18 h. While stirring. The mixture was concentrated to remove THF and the resulting precipitate was filtered and dried. Dried. Dissolve the solid in EtOH (25 ml), add 10% Pd / C (0.12 g) and suspend. H_TwoUnder a blanket for 15 hours. The reaction was filtered through celite and The filtrate was evaporated to dryness and 3-carboxamide- as a yellow oil. 5-trifluoromethylaniline was obtained. Next, this compound was added to 2-chloro-4. -Trifluoromethylpyrimidine-5-carbonyl chloride and described in Example 1 To give the title compound in 55% yield. Mp 218-219 ° C.                                Example 12 2-chloro-4-trifluoromethyl-5-N- (3'-trifluoromethyl-        5'-ethoxycarbonylphenyl) pyrimidinecarboxamide   3-Nitro-5-trifluoromethylbenzoic acid (0.36 g, 1.53 mmol) in CH_TwoCl_Two (20 ml) solution, oxalyl chloride (0.58 g, 4.60 mmol) was added, followed by DMF ( 3 drops) were added. The evolved gas was immediately discharged and the reaction was stirred for 18 hours. Reduce solvent The oil was removed under pressure and the resulting oil was dissolved in THF (80 ml) and cooled to 0 ° C. cold To the cooled solution was added EtOH (5 ml) in THF (15 ml) and the mixture was stirred at room temperature for 18 hours. Stirred. The mixture was concentrated to remove THF and the resulting precipitate was filtered, dried Was. The solid was dissolved in EtOH (25 ml), 10% Pd / C (0.12 g) was added and the suspension H_TwoUnder a blanket for 15 hours. The reaction was filtered through celite and filtered. The liquid was evaporated to dryness and 3-ethoxycarbonyl- as a yellow oil. 5-trifluoromethylaniline was obtained. Next, the compound was treated with 2-chloro-4- Trifluoromethylpyrimidine-5-carbonyl chloride and as described above To give the title compound in 12% yield. Mp 67-71 ° C.                                Example 13               2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-dichlorophenyl) -5-N- (methyl) pyrimidinecarboxamide   2-chloro-4-trifluoromethyl-5-N- (3,5-dichlorophenyl ) Pyrimidinecarboxamide (0.086 g, 0.23 mmol) in DMF (20 ml) H (0.02 g, 0.53 mmol) was added. The reaction was stirred at room temperature for 0.3 h, then MeI (0. (100 ml, 1.61 mmol) and stirring was continued for a further 2 hours. Acidify the solution with 2N HCl And then extracted with EtOAc (3 ×). MgSO 4_FourDried on Filter and remove the solvent under reduced pressure. Chromatography of the resulting oil ー （SiO_Two, 7: 1 hexane / EtOAc) to give the title compound as a white solid (6% yield). %)Obtained. 124-125 ° C.                                Example 14               2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-dichlorophenyl) -5-N- (benzyl) pyrimidinecarboxamide   Benzaldehyde (1.04 g, 9.40 mmol) in MeOH (35 ml), 3,5-dichloro A mixture of roaniline (1.71 g, 10.60 mmol) and HOAc (0.20 ml) was brought to 0 ° C. Cool. Next, NaBH_ThreeThe CN solution (28.0 ml, 28.0 mmol, 1.0 M THF solution) was The solution was dropped by a syringe pump over a period of 0.25 hours. The solution is further incubated at 0 ° C. for 0.3 hour And then stirred at room temperature for 18 hours. Excess NaBH_ThreeQuench CN with HCl and remove solvent Removed under reduced pressure. The resulting oil is EtOAc / H_TwoDissolve in O and make basic with NaOH , Extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO_FourDry on and filter And removed the solvent under reduced pressure. Chromatography of the resulting oil (SiO_Two, 15: 1 hexane / EtOAc) to give N-benzyl-3 as a white solid. , 5-Dichloroaniline was obtained. Next, the compound was treated with 2-chloro-4-trifur Olomethylpyrimidine-5-carbonyl chloride was coupled as described and Chromatography (SiO_Two, 9: 1 hexane / EtOAc) to give a white foam. The title compound (15% yield) was obtained. 102-104 ° C.                                Example 15       5-N- [3 ', 5'-bis (trifluoromethyl) phenyl]-           2,4-dichloro-6-methylpyrimidinecarboxamide   5-Carbetoxy-6-methyluracil has been described in the literature (Lamon, J. Het. Chem., 26 1, 1969). 180-182 ° C. Then add ethyl ester 2 -Hydroxy-4-methylpyrimidine-5-carboxylic acid To give 2,4-dihydroxy-6-methylpyrimidine-5-carbo Acid was obtained in 95% yield. Melting point> 230 ° C.   2,4-dihydroxy-6-methylpyrimidine-5-carboxylic acid is converted to POCl_ThreeWith And heated to reflux. The reaction mixture is concentrated and distilled to 2,4-dichloro-6-methyl Lupyrimidine-5-carbonyl chloride was obtained (boiling point 70-80 ° C, 1.5 mm / Hg). 2,4-dichloro-6-methylpyrimidine-5-carbonyl chloride (0.15 g , 0.67 mmol) was immediately converted to 3,5-bis (trifluoromethyl) aniline (0.15 g, 0.67 mmol) and reacted in the same manner as described in Example 1 to give the title compound ( 0.06 g, starting 2,4-dihydroxy-6-methylpyrimidine-5-carboxylic acid 24%). 174-176 ° C.                                Example 16           2,4-dichloropyrimidine-5-carbonyl chloride   The title compound was prepared as described in the literature (Smith and Christensen, J. Org. Chem., 20: 829, 195). As described in 5), 2,4-dihydroxypyrimidine-5-carboxylic acid Prepared starting from The above compound was obtained by distillation in a yield of 46%. Boiling point 90-100 ℃ ( 1.5 mm / Hg).¹H NMR (CDCl_Three) Δ 9.29.                                Example 17                  Ethyl ureido methylene acetoacetate   Ethyl acetoacetate (200 g, 1.54 mol), urea (105 g, 1.54 mole) And a mixture of triethyl orthoformate (228 g, 1.54 mol) at 140 ° C and N_TwoBelow 22 Heated for hours. The reaction mixture was cooled and filtered to give the title compound in 51% yield (156 g) I got it. 173-174 ° C.                                Example 18                Ethyl ureido methylene benzoyl acetate   Except for using ethyl benzoyl acetate (30 g, 156 mmol), The title compound was prepared as described in 17 to give a yield of 21% (12 g). Melting point 124-12 6 ° C.                                Example 19     Ethyl 2-hydroxy-4-methylpyrimidine-5-carboxylate   Ethyl ureido methylene acetoacetate (50 g, 250 mmol) NaOEt (22.1 g , 325 mmol) in EtOH (500 ml) at room temperature, N_TwoStirred under for 3 days. Got The solid was filtered and dried to give the title compound as a sodium salt in 88% yield (45 g). Was. Melting point> 220 ° C (decomposition).                                Example 20    Ethyl 2-hydroxy-4-phenylpyrimidine-5-carboxylate   Using ethyl ureido methylene benzoyl acetate (12 g, 45 mmol) And the title compound was prepared as described in Example 19, yielding 15% (6 g). Obtained. Melting point> 260 ° C (decomposition).                                Example 21       Ethyl 2-chloro-4-methylpyrimidine-5-carboxylate   Ethyl 2-hydroxy-4-methylpyrimidine-5-carboxylate (5 g , 27.5 mmol) and POCl_Three(84 g, 550 mmol) in N_TwoHeat reflux for 1 hour under did. The reaction was cooled and concentrated. CHCl residue_ThreeAnd H_TwoAnd the organic layer Dry (Na_TwoSO_Four), Filtered and concentrated to give the title compound in 27% (1.5 g) yield.¹ H NMR (CDCl_Three) Δ 9.04 (s, 1H), 4.42 (q, 2H), 2.85 (s, 3H), 1.43 (t, 3H ).                                Example 22      Ethyl 2-chloro-4-phenylpyrimidine-5-carboxylate   2-hydroxy-4-phenylpyrimidine-5-carboxylate (6 g, 25  The title compound was prepared as described in Example 21 except that (5.5 g, 18% yield). 45-47 ° C.                                Example 23             2-chloro-4-methylpyrimidine-5-carboxylic acid   Ethyl-2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g , 5 mmol) and NaOH (0.24 g, 6 mmol) in H_TwoO (30 ml) solution at room temperature for 3 hours Stirred. The solution was acidified with 6N HCl and the resulting solid was filtered, dried and title A compound (0.67 g, yield 78%) was obtained.¹H NMR (DMSO-d₆) Δ9.01 (s, 1H), 2.75 ( s, 3H).                                Example 24            2-chloro-4-phenylpyrimidine-5-carboxylic acid   2-chloro-4-phenylpyrimidine-5-carboxylate (4.5 g, 17 mm ol) was used to prepare the title compound as described in Example 23, except that 87% (3.9 g) was obtained. 105-110 ° C.                                Example 25        2-chloro-4-methylpyrimidine-5-carbonyl chloride   2-chloro-4-methylpyrimidine-5-carboxylic acid (0.81 g, 4.70 mmol) , Oxalyl chloride (0.89 g, 7.05 mmol) and DMF (2 drops) in CH_TwoCl_Two(23 ml) Solution at room temperature, N_TwoStirred under for 4 hours. The solution was concentrated and distilled to give the title compound (0. 55 g, 61% yield). Boiling point 90-100 ° C, 1.3 mm / Hg.¹H NMR (CDCl_Three) Δd 9.02 (S, 1 H), 2.74 (s, 3H).                                Example 26       2-chloro-4-phenylpyrimidine-5-carbonyl chloride   2-Chloro-4-phenylpyrimidine-5-carboxylic acid (3.8 g, 14 mmol) Except that used, the title compound was prepared as described in Example 25 and yield 53% Obtained. Melting point 42 [deg.] C.                                Example 27              2-chloropyrimidine-5-carbonyl chloride   The compounds were prepared according to the literature (Arukwe, J. Undhejm. K. Acta Chemica Scand., B40: 764, 1986). ).                                Example 28     Ethylethoxymethylene-4,4,4-trifluoroacetoacetate   4,4,4-trifluoroacetoacetate (46 g, 0.25 mol) orthoformate Triethyl (74 g, 0.50 mol) and Ac_TwoO (77 g, 0.75 mol) solution at 120-140 ° C For 7 hours. The mixture was concentrated and distilled to give the title compound in a yield of 98% (58.6 g). I got it. Boiling point 80-90 ° C, 1.5 mm / Hg.                                Example 29   2,4-bis (trifluoromethyl) pyrimidine-5-carbonyl chloride   Ethylethoxymethylene-4,4,4-trifluoroacetoacetate (15 g , 62.5 mmol) and trifluoroacetamidine (12.6 g, 112.5 mmol) in EtO H (50 ml) solution to N_TwoThe mixture was heated under reflux for 24 hours. The reaction mixture was cooled and concentrated . Chromatography (SiO_Two, 20% EtOAc / hexane) to give ethyl as oil Ru-2,4-bis (trifluoromethyl) pyrimidine-5-carboxylate ( 7.0 g, yield 39%).¹H NMR (CDCl_Three) Δ 9.37 (s, 1H), 3.70 (q, 2H), 1.27 (t, 3H).    EtOH (20 ml) and H_TwoEthyl-2,4-bis (trifluoromethyl) in O (50 ml) Tyl) pyrimidine-5-carboxylate (5.0 g, 17 mmol) and NaOH (0.72  g, 18 mmol) was stirred at room temperature for 1 hour. The solution was acidified (HCl) and the resulting solid Are filtered and dried to give 2,4-bis (trifluoromethyl) -pyrimidine-5-ca. Rubonic acid (1.5 g, yield 25%) was obtained. Melting point 59 ° C,¹H NMR (DMSO-d₆) Δ9.62 (s , 1H).   The desired acid chloride was prepared in a manner similar to that described in Obtained from s (trifluoromethyl) -pyrimidine-5-carboxylic acid in a yield of 44%. Boiling point 105 ° C (1.5 mm / Hg),¹H NMR (CDCl_Three) Δ 9.12 (s, 1H).                                Example 30       2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid   2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride (2.1 g, 8.6 mmol) of H_TwoO (10 ml) solution at 0 ° C, N_TwoStir for 0.5 hours under . The obtained solid was filtered and dried to give the title compound (1.91 g, yield 98%). Fusion Point 232-234 ° C (decomposition).                                Example 31   2-cyano-4-trifluoromethylpyrimidine-5-carbonyl chloride   2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (2.80 g, 1 2.4 mmol) in THF (50 ml) at 0 ° C._ThreeN (bubble for 5 minutes) ). The reaction was maintained at 0 ° C. for 0.25 hours and the resulting solid was filtered and Ammonium chloride-4-trifluoromethylpyrimidine-5-carboxylic acid (3.40 g, 97% yield). 120-121 ° C (decomposition).   DMF (36.5ml) and H_Two2-trimethylammonium chloride in O (18.3 ml) Do-4-trifluoromethylpyrimidine-5-carboxylic acid (3.62 g, 12.7 mmol) And KCN (0.99 g, 15.2 mmol) at room temperature under N_TwoStirred under for 0.25 hours. Anti The reaction mixture was concentrated and dissolved in EtOAc (400 ml). EtOAc layer H_TwoO (4 x 100ml), Washed with brine (100 ml) and dried (Na_TwoSO_Four). The EtOAc layer was filtered and concentrated To give 2-cyano-4-trifluoromethylpyrimidine-5-carboxylic acid (2.03 g, yield 74%). 148-149 ° C (decomposition).   2-cyano-4-trifluoromethylpyrimidine-5-carboxylic acid (2.0 g, 9. 2 mmol), oxalyl chloride (1.4 g, 11 mmol) and DMF (4 drops) in CH_TwoCl_Two(46ml) Bring the solution to room temperature, N_TwoStirred below for 0.75 hours. The reaction is concentrated and distilled (bp 10 (0 ° C, 1.5 mm / Hg) to give the title compound (1.8 g, yield 82%).¹H NMR (CDCl_Three) δ9.49 ( s, 1H).                                Example 32             2-phenylpyrimidine-5-carbonyl chloride   Ethyl 3-N, N-dimethylamino-2-formyl acrylate (4.0 g, 23 mm ol) (Arnold, Coll. Czech. Chem. Commun. 26: 3051, 1961), benzamidine Dissolution of hydrochloride (4.0 g, 26 mmol) and sodium (0.65 g, 28 mmol) in EtOH (40 ml) The liquid was heated at reflux for 1 hour. The solution was filtered and concentrated, and the residue was treated with EtOAc and dilute HCl (10% ). Dry the organic layer (Na_TwoSO_Four) And concentrate to ethyl 2-phenyl Pyrimidine-5-carboxylate (4.0 g, yield 75%) was obtained. Melting point> 220 ℃ ( Disassembly).   The corresponding 2-phenylpyrimidine-5-carboxylic acid was prepared as described in Example 23. From ethyl 2-phenylpyrimidine-5-carboxylate in the same manner as Prepared starting with a yield of 80% (0.35 g). Melting point> 220 ° C (decomposition).   The title compound was prepared in a similar manner to that described in Example 25 using 2-phenylpyrimido. Prepared from gin-5-carboxylic acid in quantitative yield. 135 ° C.                                Example 33          Ethyl 2-trifluoromethyl-4-hydroxypyrimidine                          -5-carboxylate   Diethyl ethoxymethylene malonate (35.0 g, 162 mmol), trifluoroacetate Toamidine (18 g, 162 mmol) and NaOEt (11.0 g, 162 mmol) in EtOH (200 ml) The liquid was heated at reflux for 6 hours. Concentrate the reaction mixture and add H_TwoO (48 ml) was added. Get The separated solid was filtered and Et_TwoO (300ml) and H_TwoWash with O (200ml), dry and title The compound (21 g, yield 50%) was obtained. Melting point> 220 ° C (decomposition);¹H NMR (DMSO-d₆) 8.3 8, 4.16 (q, 2H), 1.25 (q, 3H).                                Example 34               2-trifluoromethyl-4-chloropyrimidine                        -5-carbonyl chloride   Ethyl 2-trifluoromethyl-4-hydroxypyrimidine-5-carboxy Rate (5.00 g, 19.4 mmol) and NaOH (0.93 g, 23.3 mmol) in H_TwoO (20ml) solution Was stirred at 60 ° C. for 15 hours. Acidify the reaction (conc. HCl) and start to form a solid Concentrated. The solid is filtered and dried to give 2-trifluoromethyl-4-hydroxy. Cypyrimidine-5-carboxylic acid (2.1 g, 53% yield) was obtained.¹H NMR (DMSO-d₆) δ8 .83 (s, 1H).   2-trifluoromethyl-4-hydroxypyrimidine-5-carboxylic acid (2.0 g , 10.4 mmol), POCl_Three(32 g, 212 mmol) and SOCl_Two(25 g, 212 mmol) in 4 Heated to reflux for days. The reaction is concentrated and distilled (boiling point 90-95 ° C, 1.5 mm / Hg) to give the title The compound (2.1 g, yield 81%) was obtained.¹H NMR (CDCl_Three) δ 9.45 (s, 1H).                                Example 35              2-chloro-4-pentafluoroethylpyrimidine                        -5-carbonyl chloride   EtOH (20ml) and H_TwoEthyl 2-hydroxy-4-pentafur in O (45 ml) Oroethylpyrimidine-5-carboxylate (4.0 g, 13 mmol) and NaOH (1. (60 g, 39 mmol) was heated at reflux for 1 hour. Cool the solution and acidify (conc. HCl) did. The solid obtained is filtered and dried to give 2-hydroxy-4-pentafluoroethyl. Tylpyrimidine-5-carboxylic acid (3.3 g, 98% yield) was obtained.¹H NMR (DMSO-d₆) δ 9.90 (bs, 1H), 8.43 (s, 1H).   2-hydroxy-4-pentafluoroethylpyrimidine-5-carboxylic acid (3. 33 g, 12.9 mmol) SOCl_Two(27.7 g, 233 mmol) The solution was heated to reflux for 0.5 h. Next And POCl_Three(35.6 g, 233 mmol) was added to the reaction mixture and heating was continued for 36 hours. reaction The mixture was concentrated and distilled (boiling point 80-85 ° C., 1 mm / Hg) to give the title compound (1.2 g, yield 3). 5%).¹H NMR (DMSO-d₆) δ 9.18 (s, 1H).                                Example 36     4-trifluoromethyl-5-N- (3 ', 5'-dichlorophenyl)                         Pyrimidinecarboxamide   2-Chloro-4-trifluoromethyl- in EtOH (1.8 ml) and water (0.9 ml) 5-N- (3,5-dichlorophenyl) pyrimidinecarboxamide (0.10 g, 0.2 7 mmol), Mg_TwoO (0.024 g, 0.59 mmol) and 5% Pd / C (0.01 g) at room temperature, H_TwoStir under a blanket for 2.5 hours. Concentrate the reaction mixture and chromatograph (SiO_Two, 9% EtOAc / hexane) to give the title compound (0.05 g, 53% yield). . 189-190 ° C.                                Example 37   2-dimethylamino-4-trifluoromethyl-5-N- (3 ', 5'-                  Dichlorophenyl) pyrimidinecarboxamide   2-chloro-4-trifluoromethyl-5-N- (3,5-dichlorophenyl G) pyrimidinecarboxamide (0.13 g, 0.36 mmol) and dimethylamine (0.1 (0 g, 2.20 mmol) in MeOH was stirred at room temperature for 3 hours. Concentrate the reaction mixture, Chromatograph (SiO_Two, 5% EtOAc / hexane) to give the title compound (0.022 g, Yield 16%). 163-164 ° C.                                Example 38      2-triethylammonium chloride-4-trifluoromethyl-     5-N- (3 ', 5'-dichlorophenyl) pyrimidinecarboxamide   2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-dichlorophen Nyl) pyrimidinecarboxamide (0.10 g, 0.27 mmol) and triethylamine (0.027 g, 0.27 mmol) in dry THF was stirred for 24 hours. Filter the solid and Et_TwoO And dried to give the title compound (0.031 g, yield 24%). 158-159 ° C.                                Example 39            2-chloro-4-methyl-5-N- [3 ', 5'-bis         (Trifluoromethyl) phenyl] pyrimidinecarboxamide   2-chloro-4-methylpyrimidine-5-carbonyl chloride (0.10 g, 0.5 3 mmol), 3,5-bis (trifluoromethyl) aniline (0.12 g, 0.53 mmol) and And a solution of Amberlyst A-21 resin (0.01 g) in EtOAc (5.3 ml) were stirred at room temperature for 1 hour. Stirred. The solution was filtered, concentrated and chromatographed (SiO_Two, 10% EtOAc / hexane ) To give the title compound (0.17 g, 84% yield). 156-157 ° C.                                Example 40    2,4-dichloro-5-N- [3 ', 5'-bis (trifluoromethyl)                 Benzyl] pyrimidine-5-carboxamide   2,4-dichloropyrimidine-5-carbonyl chloride (0.10 g, 0.40 mmo l) and 3,5-bistrifluoromethylbenzylamine (0.10 g, 0.45 mmol) The title compound was prepared as described in Example 1 except that 61% (0.12 g) was obtained. 144-145 ° C.                                Example 41    2,4-dichloro-5-N- [3 ', 5'-bis (trifluoromethyl)                  Phenyl] pyrimidine-5-carboxamide   Except that 2,4-dichloropyrimidine-5-carbonyl chloride was used The title compound was prepared as described in Example 1 and the compound was obtained in 97% yield (0.28 g). Obtained. 104-105 ° C.                                Example 42      2-cyano-4-trifluoromethyl-5-N- [3 ', 5'-bis      (Trifluoromethyl) phenyl] pyrimidine-5-carboxamide   2-cyano-4-trifluoromethylpyrimidine-5-carbonyl chloride (0.11 g, 0.46 mmol), except that the title compound was used as described in Example 1. Was prepared, and the compound was obtained in a yield of 96% (0.19 g). 146-147 ° C.                                Example 43           2-chloro-4-phenyl-5-N- [3 ', 5'-bis         (Trifluoromethyl) phenyl] pyrimidinecarboxamide   2-chloro-4-phenylpyrimidine-5-carbonyl chloride (0.10 g, 0 .40 mmol), 3,5-bis (trifluoromethyl) aniline (0.08 g, 0.40 mmol) And Et_ThreeA solution of N (0.04 g, 0.40 mmol) in EtOAc was stirred at room temperature for 2 hours. solution Is concentrated and chromatographed (SiO_Two, 5% EtOH / CHCl_Three) To the title compound (0.0 8 g, yield 45%). 154 ° C.                                Example 44      2-hydrazino-4-trifluoromethyl-5-N- (3 ', 5'-             Dichlorophenyl) pyrimidine-5-carboxamide   2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-dichlorophen Nil) pyrimidinecarboxamide (0.10 g, 0.27 mmol) and hydrazine (0.009 g, 0.54 mmol) in THF._TwoThe mixture was stirred at room temperature for 14 hours. Filter the solution and concentrate Chromatograph (SiO_Two, 20% EtOAc / hexane) to give the title compound (0.0 8g, 79% yield).¹H NMR (acetone-d₆) δ 10.08 (bs, 1H), 9.64 (bs, 1H ), 8.89 (s, 1H), 7.80 (s, 2H), 7.24 (s, 1H), 2.79 (bs, 2H).                                Example 45        2- [N- (1-aminocitraconamide)]-4-trifluoromethyl-      5- [N- (3 ', 5'-dichlorophenyl)]-pyrimidine-5-carboxamide   2-hydrazino-4-trifluoromethyl-5- [N- (3 ', 5'-dichloro Rophenyl) pyrimidinecarboxamide (0.08 g, 0.21 mmol) and anhydrous citrus CHCl in conic acid (0.024 g, 0.21 mmol)_Three(2.1 ml) solution with N_TwoHeated under reflux for 24 hours did. The solution is concentrated and chromatographed (SiO_Two, 33% EtOAc / hexane) The title compound (0.06 g, yield 62%) was obtained. Mp 182-183 ° C.                                Example 46           2-phenylamino-4-trifluoromethyl-5-N-     (3 ', 5'-dichlorophenyl) -pyrimidine-5-carboxamide   2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-dichlorophen Nyl) pyrimidinecarboxamide (0.10 g, 0.27 mmol) and aniline (0.06 g, 0.59 mmol) in dry THF (2.7 ml) at room temperature_TwoStirred under for 18 hours. Reaction mixture The mixture was filtered, concentrated and chromatographed (SiO_Two, 50% CHCl_Three/ Hexane) This gave the title compound (0.10 g, yield 91%). 228-229 ° C.                                Example 47        Methyl 5-chloro-6-methyl-2-pyrazinecarboxylate   Methyl 4,5-dihydro-6-methyl-5-oxo-2-pyrazinecarboxy Rate (M. Mano, T. Seo, K. Imai, Chem. Pharm. Bull 10: 3057-3063, 1980) POCl in DMF (20 ml) solution_Three(20 ml) was added. The reaction was refluxed for 0.5 hour, then And poured into ice. CHCl aqueous layer_ThreeAnd dried (MgSO 4_Four) And concentrated. Residue Chromatograph (SiO_Two, CHCl_Three) To give the title compound (2.34 g, 52% yield). Was. Melting point 49-50 [deg.] C.                                Example 48              5-chloro-6-methyl-2-pyrazinecarboxylic acid   Methyl 5-chloro-6-methyl-2-pyrazinecarboxylate (0.16 g, 0.8 6 mmol), K_TwoCO_Three(0.31 g, 2.18 mmol) and H_TwoThe mixture of O was stirred at room temperature for 2 hours. Was. The reaction was filtered, acidified (20% HCl) and the resulting solid was collected to give the title compound (0.057 g, yield 39%) was obtained. 116-117 ° C.                                Example 49          2-chloro-5-N- (bistrifluoromethylaniline)                          Pyrazinecarboxamide   2-chloro-5-pyrazinecarboyl instead of pyrimidinecarbonyl chloride The procedure outlined in Example 1 was followed, except that nyl chloride (0.1 g, 0.57 mmol) was used. The title compound was obtained in a yield of 51% (0.08 g) using a procedure similar to the one above. Melting point 101-102 ° C.                                Example 50       2-trimethylammonium chloride-4-trifluoromethyl                         -5-pyrimidinecarboxylic acid   2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (6.0 g, 27 mmol) and an excess of trimethylamine in THF (60 ml) was stirred for 5 minutes. The solid was filtered and dried to give the title compound (7.1 g, 97% yield).¹H NMR (DMSO-d₆ ) δ 9.19 (s, 1H), 2.72 (s, 9H).                                Example 51      2-fluoro-4-trifluoromethyl-5-pyrimidinecarboxylic acid   2-trimethylammonium chloride-4-trifluoromethyl-5-pyri Midine carboxylic acid (4.3 g, 15 mmol), KF (1.8 g, 30 mmol), DMF (40 ml) and H_Two A mixture of O (20 ml) was stirred for 0.5 hours. Concentrate the mixture, acidify and Et_TwoIn O Extracted. Et_TwoThe O layer was concentrated to give the title compound (1.6 g, yield 47%).¹H NMR (DMS O-d₆) δ 9.41 (s, 1H).                                Example 52                2-fluoro-4-trifluoromethyl-5-                      Pyrimidine carbonyl chloride   2-fluoro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol), oxalyl chloride (1.0 g, 8 mmol) and DMF (2 drops) in CH_TwoCl_Two(30ml )) The title compound was prepared as described in Example 25 except that a solution was used and collected. Obtained at a rate of 75% (1.2 g).¹H NMR (CDCl_Three) δ 9.42 (s, 1H).                                Example 53     2-fluoro-4-trifluoromethyl-5-N- [3 ', 5'-bis         (Trifluoromethyl) phenyl] pyrimidinecarboxamide   2-fluoro-4-trifluoromethylpyrimidine-5-carbonyl chloride (0.05 g, 0.22 mmol) and 3,5-bis (trifluoromethyl) aniline (4 Example 5 except that a 5 mg, 0.2 mmol) solution of EtOAc (2 ml) was used. The title compound was prepared as described above and obtained in a yield of 22% (0.02 g). 133-135 ° C.                                Example 54   2-chloro-4-trifluoromethyl-5-pyrimidinecarbonyl chloride   2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7. 1 mmol) and oxalyl chloride (1.0 g, 8 mmol) in CH_TwoCl_Two(30ml) solution And the title compound was prepared as described in Example 25, and in 70% yield (1.1 g). Obtained.¹H NMR (CDCl_Three) δ 9.31 (s, 1H).                                Example 55                Synthesis of representative compounds by combinatorial chemistry technology   This example illustrates the synthesis of a representative class of compounds of the invention by combinatorial chemistry. For example. Although this example illustrates a specific class of compounds, the following procedure is It should be understood that they can be used to synthesize other compounds of the invention.   Wells 2-11 of a 96-well 1 ml plate (rows 1 and 12 are open as controls) 5 mg of Amberlyst 21 resin, 0.2 ml of EtOAc and 22.4 μmol of 8 0 different amine derivatives were added. Then, 25.0 μmol of the appropriate 5- Carbonyl chloride (for example, 2-chloro-4-trifluoromethylpyrimidi -5-carbonyl chloride) was added. Ultrasonic 96-well plate for 0.3 hours Wave treated, 50 μL H_TwoO was added to each well. The plate is sonicated for an additional 0.25 hours. The EtOAc layer was removed from each well and concentrated to give 80 separate compounds. Thin Layer chromatography, HPLC and GC / MS analysis shows that the desired compound is> 90% pure It was shown that it was generated. This approach allows for a large number of each substituted pyrimidine to be prepared. Different 5-carbonylpyrimidines that can be used to produce a number of derivatives Over 160 derivatives of each can be used to prepare routinely.                                Example 56                       Inhibition of NFκB and AP-1 activation A. NFκB assay   NFκB junction fused to the minimal SV-40 promoter driving luciferase expression Stable human Jurkat T cells containing a position (derived from the MHC promoter) were used in this experiment. Was. Cells are grown 3 x 10 every 2-3 days.^FiveCells / mL (cells in logarithmic growth phase) Cell concentration should be 1 × 10 to maintain growth⁶Cells / mL). these Of cells and 1 × 10 5 in fresh medium containing 10% Serum-Plus⁶Cell / mL density And seeded in a 96-well round bottom plate 18 hours before starting the experiment (200 μL per well).   Next, the book dissolved in dimethyl sulfoxide (3.3, 0.33 and 0.03 μg / mL) The compound of the invention is added to a 96-well plate containing cells and the plate is incubated at 37 ° C. And incubate for 0.5 hour. Then 50 ng / mL phorbol 12-myristate -13-Acetic acid (PMA) and 1 μg / mL phytohemagglutinin (PHA) were added to each well. And the cells were further incubated for 5 hours at 37 ° C. Plate at 2200 RPM , Centrifuged at room temperature for 3 minutes and then the medium was removed. 60 μL of fine Vesicle lysis buffer was added and the plates were left at room temperature for 0.25 hours. Then 40 Transfer μL of each cell extract to a black 96-well plate and add 50 μL of Lucifera Ze substrate buffer was added. Luminescence was measured immediately using a Packard TopCount. B. AP-1 assay   For AP-1, the assay was performed using collagenase promoter-driven luciferase expression. Using a stable Jurkat T cell containing a collagenase promoter driving the current NFκB, except as described above. In addition, the concentration of PMA used was 5 ng / mL. C. result   A representative compound of the present invention, 2-chloro-4-trifluoromethyl-5-N- (3 On ', 5'-bistrifluoromethylphenyl) pyrimidinecarboxamide The results of the above assays are shown in FIG. 3 as% inhibition relative to control. This figure Was also used in this assay as a control cell line showing effects on transcription. 3 shows the activity of β-actin. Loss of β-actin activity causes a transcription factor The selectivity of the test compound for offspring AP-1 and NFκB is demonstrated.   I c₅₀Results of these assays for additional test compounds, expressed as' s Are summarized in Table 2 below.   Based on the results of this experiment, representative compounds of the present invention are involved in gene transcription. Effective in inhibiting the activation of transcription factors (ie, NFκB and AP-1). Thus, for example, it has been found to have utility as an immunosuppressant.                                Example 57                            Inhibition of cytokines   To determine the effect of compounds on PMA / PHA-induced cytokine production, Any of the NFκB (for IL-8) and AP-1 (for IL-2) reporters of Example 56 -Supernatants were collected from the gene assays and stored. Cytokine levels in the supernatant Bells (25-50 μL aliquots) were determined by ELISA. Representative compounds of the present invention 2-chloro-4-trifluoromethyl-5-N- (3 ', 5'-bistrifluoro Figure 4 shows the results of this experiment for (romethylphenyl) pyrimidinecarboxamide. Shown (expressed as% of control).                                Example 58                       In vivo activity of representative compounds   The mouse popliteal lymph node (PLN) assay is a compound that blocks human transplant rejection. A graft-versus-host model that predicts the activity of a product. Oxazolone Delayed type hypersensitivity response is a standard contact sensitivity model. Both of these models Is used routinely to evaluate clinically used compounds. For example, cyclo Sporin and cyclophosphamide are active in these models and (Morris et al., Transplantation Proceedings 22 (Suppl. 1) 110). -112, 1990). A. Popliteal lymph node model   The spleen is removed from the donor BALB / c mouse and the spleen cells are isolated and then (3,000 rad) to prevent donor cell growth. After washing and adjusting cell density, 2.5 × 10⁶Were subcutaneously injected into the left hind footpad of C3H mice. On day 4, the mice were sacrificed And the left popliteal lymph node (PLN) was weighed.   2-chloro-4-trifluoromethyl-5-N- (3 ′, 5 ′) which is the compound of Example 1 -Bistrifluoromethylphenyl) pyrimidinecarboxamide was administered via footpad injection (0 Administered once daily by intraperitoneal injection, starting one day before day 4) until day 4. Use Immediately before use, the compounds were prepared at a concentration of 5 mg / mL using a glass-Teflon homogenizer. Suspended in 25% methylcellulose (Sigma). For doses of 10, 20, and 30 mg / kg Make an appropriate dilution of the stock solution and inject 0.1 mL / 10 g body weight intraperitoneally. Was administered.   The results of this experiment, shown in FIG. 5, indicate that the representative compound of the present invention is a It demonstrates that it causes a dose-dependent suppression of proliferation. The lowest dose of this compound ( 10 mg / kg) resulted in a 52% inhibition of growth, whereas cyclosporin A was 3 mg at 12 mg / kg. A 5% inhibition occurred. B. Delayed type hypersensitivity research   On day 0, oxazolone (100 μL of a 3% solution) was applied to the shaved abdomen of the mice. Was. On day 7, an oxazolone challenge was applied around the right ear (10 μL). The compound of Example 1, 2-chloro-4-trifluoromethyl-5-N- (3,5-bi (Trifluoromethylphenyl) pyrimidinecarboxamide by intraperitoneal injection. On days 2-7. This is done immediately before use with a glass-Teflon homogenizer. Prepared by suspending in 0.25% methylcellulose (Sigma) did. For each dose, a suspension of 0.1 mL / 10 g body weight was administered. Compound is the research And make the appropriate dilution of the stock solution into 0.1 ml / 10 It was made so that g body weight was administered. After 24 hours, measure the difference in thickness between the right and left ears did. The results of this experiment are shown in Table 3 below. * One animal died during the study.   Test compound (30 mg / kg i.p.) and cyclophosphamide (50 mg / kg i.p.) 56% and 73%, respectively, significantly reduced the delayed response to oxazolone.   Although particular embodiments of the present invention have been described herein for purposes of illustration, various modifications may be made. Can be made without departing from the spirit and scope of the invention. .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 239/42 C07D 239/42 Z 241/24 241/24 241/34 241/34 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), UA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IL, IS, JP, KE, KG , KP, R, KZ, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK , TJ, TM, TR, TT, UA, UG, US, UZ, VN (72) Inventor Goldman, Mark E. California 92130, San Diego, Corte de la Fonda 4372 (72) Inventor Gayo, Rare M United States California 92129, San Diego, Manix Road 12555 (72) Inventor Lanzon-Fon, Lin Jay. United States California 92130, San Diego, Carwood Court 4209 (72) Inventor Paranki, Moody S. S. United States California 92024, Encinitas, Crest Drive 602 (72) Inventor Sullivan, Robert W. United States California 92054, Oceanside, Mountain Vista Way 2035

Claims (1)

[Claims] 1. Compounds having the following structures, including pharmaceutically acceptable salts thereof: here   R_FiveIs selected from the following chemical moieties:   R₇Is hydrogen, -CH_Three, And -CH_TwoC₆H_FiveSelected from;   R₈Is hydrogen and unsubstituted or substituted C_1-8Alkyl, C_6-12Aryl, C_{7- 12} Aralkyl, C_3-12Heterocycle and C_4-20Selected from heterocyclic alkyl;   R_2aIs halogen, unsubstituted or substituted C_1-8Alkyl, C_6-12Aryl, C_{7 -12} Aralkyl, C_3-12Heterocycle or C_4-20Heterocyclic alkyl, -CN, -OR, Selected from -NRR, and -NRNCOR;   R_4aIs hydrogen, halogen, unsubstituted or substituted C_1-8Alkyl, C_6-12Ally Le, C_7-12Aralkyl, C_3-12Heterocycle or C_4-20Heterocyclic alkyl, -CN,- OR, -NRR and -NRNCOR; and   R₆Is hydrogen, halogen and unsubstituted or substituted C_1-8Selected from alkyl ;   And here   Each R is independently unsubstituted or substituted C_1-8Alkyl, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle or C_4-16Selected from heterocyclic alkyl;   Where: (a) R_FiveIs CONR₇R₈If it is, (I) R₇And R₈Are not both hydrogen. (Ii) R_2aIs -N (CH_Three)_Two, -N (CH_TwoCH_Three)_Two, -OR, and unsubstituted Chain or branched acyclic saturated C_1-3Alkyl, -N (CH_Three)_Two, -N (CH_TwoCH_Three )_TwoAnd -OR, (Iii) R_2aIs -Cl, and R₆Is -H, R_4aIs -CF_Three, -C 1, -CH_ThreeAnd -C (CH_Three)_ThreeNot selected from (IV) R_2aIs -Cl, and R_4aAnd R₆And both are -H, then R₈Is- CH (CN) C₆H_FiveNot, and (V) R_2aIs -Cl, and R_4aIs -Cl, R₆Is -Cl and -CH_TwoNot selected from Cl; and   (B) R_FiveIs -N (R₇) C (= O) R₈If it is, (I) R_2aIs -CH_Three, -OCH_ThreeAnd -N (CH_Three)_TwoNot selected from, and (Ii) R₈Is -H and -CH_ThreeNot selected from 2. A compound according to claim 1 having the following structure: 3. R_4aIs -CF_Three, -Cl, -F, -CH_ThreeAnd -H 3. The compound according to 2. 4. R_2aIs -Cl, -OCH_Three, -H, -N (CH_Three)_Two, -CF_Three, -CN, -N HNH_TwoAnd -NHC₆H_FiveThe compound according to claim 2, which is selected from: 5. R₆Is -H, -CF_Three, -CH_ThreeAnd -Cl. Listed compound. 6. R₇Is -H and -CH_ThreeThe compound according to claim 2, which is selected from: 7. R₈The compound of claim 2, wherein is Wherein X, Y and Z may be the same or different and are independently hydrogen , -OH, -R, -OR, -COOH, -COOR, -COR, -CONH_Two, -NH_Two, -NHR, -NRR, -SH, -SR, -SOOR, -SO_ThreeR and -Selected from SOR. 8. R_4aIs -CF_ThreeAnd R_2a3. The compound of claim 2, wherein is -Cl. 9. R_4aIs -CF_ThreeThe compound of claim 2, which is 10. The compound is 2-fluoro-4-trifluoromethyl-5-N- (3 ' , 5'-bistrifluoromethyl) pyrimidinecarboxamide, 5- (3 ', 5 '-Bis (trifluoromethyl) phenacyl) -2-methoxy-4-trifluoro L-methylpyrimidine; 4-trifluoromethyl-5-N- (3 ', 5'-dichloro Rophenyl) pyrimidinecarboxamide; 2-dimethylamino-4-trifluoro Romethyl-5-N- (3 ', 5'-dichlorophenyl) pyrimidinecarboxami 2-triethylammonium chloride-4-trifluoromethyl-5-N -(3 ', 5'-dichlorophenyl) pyrimidinecarboxamide; 2-cyano- 4-trifluoromethyl-5-N- [3 ', 5'-(bistrifluoromethyl) Phenyl] pyrimidinecarboxamide; 2-hydrazino-4-trifluoromethyl Ru-5- [N- (3 ', 5'-dichlorophenyl) pyrimidine-5-carboxa Mido; 2- [N- (1-aminocitraconamide)]-4-trifluoromethyl -5- [N- (3 ', 5'-dichlorophenyl) pyrimidine-5-carboxami And 2-aminophenyl-4-trifluoromethyl-N- (3 ', 5'- 10. Dichlorophenyl) pyrimidine-5-carboxamide. The compound according to the above. 11. R_2a3. The compound of claim 2, wherein is -Cl. 12. The compound is represented by the formula: 5-N- [3 ', 5'-bis (trifluoromethyl) Nyl] -2,4-dichloro-6-methyl-pyrimidinecarboxamide; 2-chloro B-4-Methyl-5-N- [3 ', 5'-(bistrifluoromethyl) phenyl ] Pyrimidinecarboxamide; 2,4-dichloro-5-N- [3 ', 5'-bis (Trifluoromethyl) benzyl] pyrimidine-5-carboxamide; and 2 -Chloro-4-phenyl-5-N- [3 ', 5'-(bistrifluoromethyl) A compound according to claim 11, which is selected from [phenyl] pyrimidinecarboxamide. Stuff. 13. R₈Is a 3,5-disubstituted phenyl moiety, and both of the substituents are electron-withdrawing groups. The compound of claim 2, which is 14． Both of the above substituents are -CF_Three14. The compound of claim 13, which is 15. At least one of the substituents is -CF_Three14. The compound according to claim 13, which is Stuff. 16. R_4aIs -H, -CH_Three, -CF_Three, -CF_TwoCF_Three, -C₆H_FiveAnd -CH_Two C₆H_FiveThe compound according to claim 2, which is selected from: 17． R_2aIs -Cl, -F, -CN and -CF_ThreeClaim 2 which is selected from A compound as described. 18. R_2a3. The compound of claim 2, wherein is selected from -Cl and -F. 19. R₆Is -H. 20. Compounds having the following structures, including pharmaceutically acceptable salts thereof: here   R_FiveIs selected from the following chemical moieties:   R₇Is hydrogen, -CH_Three, And -CH_TwoC₆H_FiveSelected from;   R₈Is hydrogen and unsubstituted or substituted C_1-8Alkyl, C_6-12Aryl, C_{7- 12} Aralkyl, C_3-12Heterocycle and C_4-20Selected from heterocyclic alkyl;   R_2bIs halogen;   R_4bIs hydrogen, halogen, -CN and unsubstituted or substituted C_1-8Alkyl, C_6-12Aryl, C_7-12Aralkyl, C_3-12Heterocycle or C_4-20Heterocyclic alkyl Selected from; and   R₁Is hydrogen, -CH_Three, -CF_ThreeAnd -CH_TwoCH_ThreeSelected from;   And here   Each R is independently unsubstituted or substituted C_1-8Alkyl, C_6-12Aryl, C_{7 -12} Aralkyl, C_3-12Heterocycle or C_4-16Selected from heterocyclic alkyl;   Where R_FiveIs -CONR₇R₈And R_2bIs -Cl, R_4bAnd R₁Is Not both are hydrogen. 21. R_4bIs unsubstituted C_1-821. The compound of claim 20, which is an alkyl. 22. R_2b21. The compound of claim 20, wherein is selected from -Cl and -F. 23. R₁Is -H and -CH_Three21. The compound according to claim 20, which is selected from: 24. R₇Is -H and -CH_Three21. The compound according to claim 20, which is selected from: 25. R₈21. The compound of claim 20, wherein is: Wherein X, Y and Z may be the same or different and are independently hydrogen , -OH, -R, -OR, -COOH, -COOR, -COR, -CONH_Two, -NH_Two, -NHR, -NRR, -SH, -SR, -SOOR, -SO_ThreeR and -Selected from SOR. 26. R_4bIs -CF_ThreeAnd R_2bIs -Cl. Compound. 27. R_4bIs -CF_Three21. The compound of claim 20, which is 28. R_2b21. The compound of claim 20, wherein is -Cl. 29. R₈Is a 3,5-disubstituted phenyl moiety, and both of the substituents are electron-withdrawing groups. 21. The compound of claim 20, which is 30. Both of the above substituents are -CF_Three30. The compound of claim 29, which is 31. At least one of the substituents is -CF_Three30. The compound of claim 29, wherein Stuff. 32. R_4bIs -H, -CH_Three, -CF_Three, -CF_TwoCF_Three, -C₆H_FiveAnd -CH_Two C₆H_Five21. The compound according to claim 20, which is selected from: 33. R₁21. The compound of claim 20, wherein is -H. 34. A compound according to claim 1 to 33 and a pharmaceutically acceptable carrier or A composition comprising a diluent. 35. A compound according to claims 1-33 and a pharmaceutically or prophylactically acceptable key. A composition comprising a carrier or a diluent. 36. Use of a compound according to claims 1-33 as active therapeutic substance. 37. 34. The method according to claims 1-33 for the manufacture of a medicament for treating an inflammatory condition. Use of compounds. 38. 38. The use according to claim 37, wherein said inflammatory condition is an immunoinflammatory condition. 39. The immunoinflammatory condition may be associated with rheumatoid arthritis, osteoarthritis, transplant rejection, 39. The use according to claim 38, wherein the use is selected from blood, ARDS and asthma. 40. 39. The use according to claim 38, wherein said immunoinflammatory condition is rheumatoid arthritis. 41. 38. The use according to claim 37, wherein said inflammatory condition is an autoimmune disease. 42. Wherein the autoimmune disease is multiple sclerosis, psoriasis, inflammatory bowel disease, glomerulonephritis, 42. The use according to claim 41, wherein the use is selected from lupus, uveitis and chronic hepatitis. 43. If the inflammatory condition is trauma, oxidative stress, cell death, radiation damage, ischemia, reperfusion 38. The use according to claim 37, wherein the use is selected from, cancer and viral infections. 44. 38. The use according to claim 37, wherein said inflammatory condition is transplant rejection.